Fatigue of respiratory muscles may play a major role in respiratory failure that develops in patients with pulmonary diseases. However, the mechanisms of muscle dysfunction and interactions of the respiratory muscles during respiratory failure remain poorly understood. In addition, the effects of arterial blood gas and acid-base alterations due to respiratory failure on respiratory muscle function are uncertain. We hypothesize that 1) mechanisms other than peripheral fatigue of the diaphragm are involved in respiratory failure due to an increased work of breathing and 2) that arterial blood gas and acid-base alterations due to respiratory failure induce respiratory muscle dysfunction by mechanisms separate from an increased work of breathing and accelerate the development of respiratory failure. Utilizing a rabbit model of respiratory failure induced by incremental inspiratory loading, the mechanisms of respiratory muscle dysfunction contributing to respiratory failure will be elucidated. Diaphragm and intercostal muscle forces will be isolated, high- and low-frequency muscle fatigue will be assessed and the effects of metabolic alterations during respiratory failure will be determined. Central drive to the diaphragm and intercostals will then be evaluated and the effects of endorphins, vagal afferents, phrenic afferents and metabolic alterations will be probed. In addition, arterial blood gas and acid-base alterations will be manipulated to ascertain their actions on respiratory muscle function and respiratory failure. Although corticosteroids are known to be capable of inducing a myopathy in peripheral skeletal muscles, little is known about their effect on respiratory muscles. Since corticosteroids in high doses and for prolonged periods are frequently utilized in the treatment of respiratory illnesses, they may accelerate respiratory failure in some patients. We hypothesize that 3) corticosteroids induce respiratory muscle dysfunction by altering respiratory muscle metabolism and accelerate the development of respiratory failure. Utilizing a rabbit model of corticosteroid myopathy and respiratory failure, the effects of corticosteroids on respiratory muscle histopathology, biochemistry and physiology at rest and during respiratory failure will be characterized. Specific mechanisms of respiratory muscle dysfunction induced by corticosteroids and their contribution to respiratory failure will then be investigated. These studies will provide added insight into the contribution and mechanisms of respiratory muscle dysfunction leading to respiratory failure as well as the action of corticosteroids on respiratory muscles and their potential contribution to respiratory failure. This should yield a better basis for the management of respiratory failure and a more efficacious usage of corticosteroids.